Technical Commentary

TECHNICAL COMMENTARY

Perospirone

Introduction in symptoms and adverse effects - can vary Second generation antipsychotics (sometimes between individuals. referred to as ‘atypical’ antipsychotics) are a Method newer class of antipsychotic medication than first generation ‘typical’ antipsychotics. Second Owing to the vast number of reviews on generation antipsychotics are effective for the antipsychotics, we have included only positive symptoms of schizophrenia. It is information reported in the abstracts of 2 sometimes claimed that they are more effective Cochrane systematic reviews . This is because than first generation antipsychotics in treating the Cochrane internal review process ensures a the negative symptoms of schizophrenia, high level of scientific rigor and meta-analyses although the evidence for this is weak. Negative are usually conducted, giving treatment effect symptoms include a lack of ordinary mental sizes. Data from the abstracts were activities such as emotional expression, social supplemented from the full text when engagement, thinking and motivation, whereas clarification was required. When multiple copies positive symptoms include the experiences of of reviews were found and/or when findings perceptual abnormalities (hallucinations) and conflict, we present the most recent version and fixed, false, irrational beliefs (delusions)1. the most recent conclusions. Where no Second generation antipsychotics may also Cochrane review exists, other reviews with cause less extra-pyramidal side effects. These pooled data are included. include dyskinesias such as repetitive, Evidence was graded using the Grading of involuntary, and purposeless body or facial Recommendations Assessment, Development movements, Parkinsonism (cogwheel muscle and Evaluation (GRADE) Working Group rigidity, pill-rolling tremor and reduced or approach where high quality evidence such as slowed movements), akathisia (motor that gained from RCTs may be downgraded to restlessness, especially in the legs, and moderate or low if review and study quality is resembling agitation) and dystonias such as limited, if there is inconsistency in results, muscle contractions causing unusual twisting of indirect comparisons, imprecise or sparse data parts of the body, most often in the neck. These and high probability of reporting bias. It may effects are caused by the dopamine receptor also be downgraded if risks associated with the antagonist action of these drugs. One intervention or other matter under review are explanation for differences in producing these high. Conversely, low quality evidence such as side effects is that high potency first generation that gained from observational studies may be antipsychotics are usually selective dopamine upgraded if effect sizes are large, there is a receptor antagonists with a high affinity for the dose dependent response or if results are dopamine receptor and they induce reasonably consistent, precise and direct with extrapyramidal effects by the blockade of these low associated risks3. The resulting table dopamine receptors. In contrast, second represents an objective summary of the generation antipsychotics generally have a evidence, although the conclusions are solely lower affinity for the dopamine receptor and the opinion of staff of NeuRA (Neuroscience also block serotonin receptors, both of which Research Australia). mechanisms may play a role in mitigating the effects of dopamine blockade. Results

This table summarises overall group We found one review that met our inclusion 4 effectiveness of perospirone, however criteria . individual treatment programs need to be tailored by trained clinicians as response - both

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Perospirone

Compared to first generation antipsychotics

Efficacy: Moderate to low quality evidence (small sample) suggests perospirone may be more effective than haloperidol for negative symptoms.

Adverse effects: Moderate to high quality evidence (medium-sized sample, consistent, precise, direct) suggests perospirone may cause fewer extrapyramidal symptoms than aripiprazole, haloperidol, and risperidone (data combined).

Compared to second generation antipsychotics

Efficacy: Moderate quality evidence (medium to large samples, mostly inconsistent, precise, direct) suggests perospirone may be less effective for symptoms than other second generation antipsychotics.

Kishi T, Nakao I. Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs 2013, 27(9):731–741

This review includes 2 double-blind and 3 open label RCTs (N = 562) that compared perospirone with olanzapine, quetiapine, risperidone, aripiprazole, haloperidol or mosapramine for 4-12 weeks. Compared to all antipsychotics combined, perospirone was inferior in the reduction of PANSS total scores (SMD 0.36, 95%CI 0.01 to 0.70, p = 0.04, I2 71%, p = 0.0006), and PANSS positive subscale scores (SMD 0.34, 95%CI 0.03 to 0.65, p = 0.03, I2 69%, p = 0.004). No differences were reported on PANSS negative, PANSS general subscale scores, discontinuation due to any cause, or inefficacy. Compared to second generation antipsychotics (olanzapine, quetiapine, risperidone, aripiprazole, or mosapramine), perospirone was inferior in the reduction of PANSS total scores (4 RCTs, N = 417, SMD 0.46, 95%CI 0.08 to 0.85, p = 0.02, I2 73%, p = 0.003), PANSS positive (SMD 0.42, 95%CI 0.03 to 0.80, p = 0.03, I2 72%, p = 0.003), PANSS negative (SMD 0.52, 95%CI 0.09 to 0.95, p = 0.02, I2 78%, p = 0.0004) and PANSS general subscale scores (SMD 0.37, 95%CI 0.04 to 0.70, p = 0.03, I2 62%, p = 0.02). Compared to haloperidol, perospirone was superior in reducing PANSS negative subscale scores (1 RCT, N = 145, SMD -0.41, 95%CI -0.74 to -0.05, p = 0.01), with no differences on any other PANSS scale.

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Perospirone

Risks Perospirone had lower scores relating to extrapyramidal symptoms than aripiprazole, haloperidol, and risperidone (3 RCTs, N = 292, SMD -0.30, 95%CI -0.53 to -0.07, p = 0.01, I2 0%, p = 0.43). No differences were reported for discontinuation due to side effects, akathisia, anxiety, at least one side effect, bradycardia, chest pain, constipation, depression, disturbance in gait, disturbance of speech, disturbance of swallowing, dizziness, dry mouth, dyskinesia, dystonia, dysuria, ejaculation disorder, epigastric distress, psychomotor excitement, fatigue, fever, headache, hyperprolactinemia, hypersalivation, hypertension, hypotension, increased appetite, insomnia, loss of appetite, mask-like face, nausea/vomiting, powerlessness, rigidity, skin problem, sleepiness, sedation, sweating, and tremor.

Consistency in results‡ Inconsistent, apart from extrapyramidal symptoms.

Precision in results§ Precise

Directness of results║ Direct

Explanation of acronyms

CI = Confidence Interval, I² = the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance), N = number of participants, p = statistical probability of obtaining that result (p < 0.05 generally regarded as significant), PANSS = Positive and Negative Syndrome Scale, SMD = standardised mean difference, RCT = randomized controlled trial

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Perospirone

Explanation of technical terms between variables. They are an indication of prediction, but do not confirm causality due to † Different effect measures are reported by possible and often unforseen confounding different reviews. variables. An r of 0.10 represents a weak association, 0.25 a medium association and Weighted mean difference scores refer to 0.40 and over represents a strong mean differences between treatment and association. Unstandardised (b) regression comparison groups after treatment (or coefficients indicate the average change in occasionally pre to post treatment) and in a the dependent variable associated with a 1 randomised trial there is an assumption that unit change in the independent variable, both groups are comparable on this measure statistically controlling for the other prior to treatment. Standardised mean independent variables. Standardised differences are divided by the pooled regression coefficients represent the change standard deviation (or the standard deviation being in units of standard deviations to allow of one group when groups are homogenous) comparison across different scales. which allows results from different scales to be combined and compared. Each study’s mean difference is then given a weighting depending on the size of the sample and the ‡ Inconsistency refers to differing estimates variability in the data. 0.2 represents a small of effect across studies (i.e. heterogeneity or effect, 0.5 a medium effect, and 0.8 and over variability in results) that represents a large effect2. is not explained by subgroup analyses and therefore reduces confidence in the effect Odds ratio (OR) or relative risk (RR) refers to the probability of a reduction (< 1) or an estimate. I² is the percentage of the variability increase (> 1) in a particular outcome in a in effect estimates that is due to heterogeneity treatment group, or a group exposed to a risk rather than sampling error (chance) - 0% to factor, relative to the comparison group. For 40%: heterogeneity might not be important, example, a RR of 0.75 translates to a 30% to 60%: may represent moderate reduction in risk of an outcome of 25% heterogeneity, 50% to 90%: may represent relative to those not receiving the treatment or considerable heterogeneity and over this is not exposed to the risk factor. Conversely, a considerable heterogeneity. I² can be RR of 1.25 translates to an increased risk of calculated from Q (chi-square) for the test of 25% relative to those not receiving treatment heterogeneity with the following formula2; or not having been exposed to a risk factor. A RR or OR of 1.00 means there is no difference between groups. A medium effect is considered if RR > 2 or < 0.5 and a large

effect if RR > 5 or < 0.25. lnOR stands for logarithmic OR where a lnOR of 0 shows no difference between groups. Hazard ratios § Imprecision refers to wide confidence measure the effect of an explanatory variable intervals indicating a lack of confidence in the on the hazard or risk of an event. effect estimate. Based on GRADE recommendations, a result for continuous Correlation coefficients (eg, r) indicate the data (standardised mean differences, not strength of association or relationship weighted mean differences) is considered

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Perospirone

imprecise if the upper or lower confidence limit crosses an effect size of 0.5 in either direction, and for binary and correlation data, an effect size of 0.25. GRADE also recommends downgrading the evidence when sample size is smaller than 300 (for binary data) and 400 (for continuous data), although for some topics, these criteria should be relaxed6.

║ Indirectness of comparison occurs when a comparison of intervention A versus B is not available but A was compared with C and B was compared with C, which allows indirect comparisons of the magnitude of effect of A versus B. Indirectness of population, comparator and/or outcome can also occur when the available evidence regarding a particular population, intervention, comparator, or outcome is not available and is therefore inferred from available evidence. These inferred treatment effect sizes are of lower quality than those gained from head-to- head comparisons of A and B.

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TECHNICAL COMMENTARY

Perospirone

References

1. Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database of Systematic Reviews. 2009; (1): CD000059. 2. CochraneCollaboration. Cochrane Handbook for Systematic Reviews of Interventions. 2008: Accessed 24/06/2011. 3. GRADEWorkingGroup. Grading quality of evidence and strength of recommendations. British Medical Journal. 2004; 328: 1490. 4. Kishi T, Iwata N. Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2013; 27(9): 731-41. 5. Rosenthal JA. Qualitative Descriptors of Strength of Association and Effect Size. Journal of Social Service Research. 1996; 21(4): 37-59. 6. GRADEpro. [Computer program]. Jan Brozek, Andrew Oxman, Holger Schünemann. Version 32 for Windows. 2008.

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